Integrated multi-omic profiling of azacitidine-venetoclax in AML reveals additional targetable pathways to improve the treatment

• The combination of venetoclax and azacitidine constitutes the first-line option for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Azacitidine-venetoclax has shown pronounced clinical and preclinical ecacy but the molecular mechanisms causing this synergy remain to be clarified. We applied an integrative multi-omic approach with focus in epigenetics on two AML cell lines to characterize the effects of azacitidine-venetoclax in vitro on chromatin accessibility, DNA methylation and gene expression patterns.We report distinct epigenetic and transcriptomic eects when combining azacitidine and venetoclax as compared to either substance alone. With the application of ATAC-seq, we delineate combination-unique gained pathways including the activation of mRNA splicing and NOTCH-HSF1 signaling but also more widespread heterochromatin compared to azacitidine or venetoclax alone. When assessing methylation status, we observed combination-unique hypermethylation of Rac1- and Rho-associated signaling. We integrate the epigenetic alterations of azacitidine-venetoclax with RNA-seq data and report activation of genes involved in the serine synthesis pathway and NTRK signaling that represent potentially upregulated survival pathways upon azacitidine-venetoclax exposure.We also propose potential synergistic triplet therapies based on in silico drug predictions using condition-wise weighted co-expression networks including inhibitors of proteaseomes, MCL-1 and histone deacetylase. Future studies are needed to investigate whether the inhibition of the mentioned pro-survival pathways or proposed triplets may enhance the effects of azacitidine-venetoclax in AML.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

Nyckelord

Azacitidine

Venetoclax

Acute myeloid leukemia

ATAC-seq

RNA-seq

Methylation

Multi-omics

In silico drug predictions

Medicinsk vetenskap

Medical Science

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)